Use of anecortave acetate for the protection of visual acuity in patients with age related macular degeneration

ABSTRACT

The present invention is directed to the use of anercortave acetate or the alcohol thereof for the protection of visual acuity in patients with age related macular degeneration.

This application claims priority from U.S. Ser. No. 60/401,220, filedAug. 5, 2002.

The present application is directed to the use of anecortave acetate tomaintain vision and provide protection of visual acuity in patients withage related macular degeneration (AMD).

BACKGROUND OF THE INVENTION

AMD is currently the primary cause of functional blindness in patientsover the age of 50 in developed countries. Although the exudative formis present in only 15-20% of the AMD population, exudative AMD accountsfor much of the significant vision loss (1). Until recently, the onlyapproved treatment for CNV associated with exudative AMD was laserphotocoagulation. In 2000, photodynamic therapy with Visudyne® wasapproved for the treatment of selected subfoveal lesions in this patientpopulation. However, this treatment option has been shown to delay, butnot stop, loss of vision in a great majority of the patients treated(2).

Because irreversible retinal damage due to exudative AMD is the directresult of abnormal choroidal blood vessel growth beneath the retinaand/or the retinal pigment epithelium (RPE), a number of angiostaticagents are now being evaluated clinically for use in treating thisblinding disorder. Angiogenesis is a complex of inter-related processeswith numerous potential opportunities for therapeutic intervention. Incontrast to other experimental therapies for AMD, which were designed tospecifically inhibit angiogenesis stimulated by vascular endothelialgrowth factor (VEGF) (3,4), anecortave acetate inhibits blood vesselgrowth by inhibiting the proteases necessary for vascular endothelialcell migration (5,6). Anecortave acetate is unique in that it inhibitsangiogenesis subsequent to (and therefore independently of) the actualangiogenic stimulus, and it therefore has the potential tononspecifically inhibit angiogenesis driven by the wide variety of knownocular angiogenic stimuli (7). The ability of anecortave acetate toinhibit angiogenesis independently of the initiating stimulus issupported by a large body of preclinical evidence, including multipleanimal models of neovascularization (6, 8-10).

SUMMARY OF THE INVENTION

The present invention is directed to preparations and methods for theprevention of the loss of visual acuity associated with AMD, themaintenance of visual acuity in persons suffering from AMD, and theinhibition of lesion growth associated with AMD. The preparations andmethods involve 3-30 mg. of anecortave acetate or its correspondingalcohol administered juxtasclerally providing for transcleral deliveryof the drug.

BRIEF DESCRIPTION OF THE DRAWINGS

Figure Legends:

Table 1. Eligibility criteria for patient enrollment in this study

Table 2. Baseline characteristics of patients enrolled in this study. Nosignificant differences between treatment groups were identified for anyparameter.

Table 3. Log MAR visual acuity changes from Baseline at Month 6 acrosstreatment groups expressed as log MAR lines of worsening or improvement.There is a clear trend favoring treatment with a single administrationof anecortave acetate 15 mg over placebo treatment for prevention ofclinically significant vision loss, defined as a worsening by ≧3 log MARlines of vision or 15 log MAR letters (12% versus 30%) from Baseline.

Table 4. Analysis of severe vision loss at Month 6 compared withBaseline among treatment groups. Treatment with Anecortave acetate 15 mgis statistically superior to placebo treatment (p=0.0224) for preventionof severe vision loss, defined as a worsening by ≧6 log MAR lines ofvision or 30 log MAR letters.

FIG. 1. When mean change from Baseline log MAR visual acuity at Month 6is compared among treatment groups, there is a statistically significantdifference (p=0.0032) between treatment with anecortave acetate 15 mgand placebo treatment. After a single treatment of anecortave acetate 15mg, mean log MAR vision changes at Month 6 by less than 1 line (by 4 logMAR letters) to a +0.08 log MAR score. In contrast, after a singleplacebo treatment the mean log MAR vision had worsened by more than 2lines (by 12 log MAR letters) to a +0.24 log MAR score over the sameperiod. This difference in Month 6 mean log MAR scores is statisticallysignificant (p=0.0032)

FIG. 2. Comparison of all 128 patients in the four treatment groups asto preservation of vision at Month 6, defined as a decrease of less than3 log MAR lines or 15 log MAR letters from Baseline values. Althoughstatistical significance is not achieved in this analysis, there is aclear trend favoring the anecortave acetate 15 mg treatment group overplacebo treatment.

FIG. 3. Subgroup analysis comparing the effect of the four treatmentgroups for preservation of vision at Month 6 in patients withpredominantly classic lesions at Baseline. There is statisticalsignificance (p=0.0209) when the anecortave acetate 15 mg treatmentgroup is compared with placebo treatment for this large subgroup ofpatients.

FIG. 4. The percentage of patients with improved vision, defined as anincrease of at least 2 log MAR lines or 10 log MAR letters of visualacuity at Month 6 compared with Baseline values. This overall analysisof all 128 patients enrolled in the study reveals a statisticallysignificant positive effect of anecortave acetate 15 mg for improvementof vision at Month 6 (p=0.025) compared with placebo.

FIG. 5. An overall analysis of the percent change in lesion growth atMonth 6 compared with Baseline. There is a statistically significantpositive effect of anecortave acetate 15 mg compared with placebo forinhibition of the total lesion growth (p=0.0005), the total CNVcomponent (p=0.0001), and the classic CNV component (p=0.0008).

DETAILED DESCRIPTION OF THE INVENTION

Anecortave acetate (4,9(11)-pregnadien-17α,21-diol-3,20 dione-21acetate) is being clinically evaluated as monotherapy to treat exudativesubfoveal AMD in this ongoing multi-center trial. The results of aninterim analysis of the first 6 months of clinical data on safety andefficacy following a single treatment are reported here.

This ongoing trial was initiated to compare the clinical efficacy ofanecortave acetate versus placebo treatment for preservation(maintenance) of vision and inhibition of CNV lesion growth. Patientswith a log MAR visual acuity of 0.3 (20/40 Snellen equivalent) to 1.2(20/320 Snellen equivalent) and primary or recurrent subfoveal choroidalneovascularization (CNV) secondary to AMD with a lesion up to 30.48 mm²(12 disc areas) in size were enrolled. Inclusion and exclusion criteriafor this study are listed in Table 1. At Baseline and follow-up visits,best-corrected log MAR visual acuity was obtained on all patients usingguidelines previously established for the Early Treatment DiabeticRetinopathy Study. Patient lesion eligibility for this study wasdetermined from standardized fluorescein angiograms at the DigitalAngiography Reading Center (DARC) by certified Readers (trained retinaspecialists) prior to enrollment and treatment. The DARC also evaluatedchanges from Baseline in the fluorescein angiographic characteristics ofthe lesions in masked fashion. Each data point represents the average ofat least two independent evaluations by DARC Readers. Because allangiographic data for this study is being collected using the samefundus camera and digital camera systems and stored as uncompresseddigital images, the actual lesion surface areas can be more closelyapproximated in mm² rather than requiring the disc area “best-fit”estimates previously used for film angiographic data.

The 128 patients in this double-masked, dose-response study wereenrolled and treated between April 1999 and May 2001 by 18 participatingsites in the US and EU. Prior to treatment, patients were enrolled andequally randomized to anecortave acetate sterile suspension forinjection 30 mg (N=33), 15 mg (N=33), or 3 mg (N=32) or to placebo(vehicle, N=30). Masking of the clinical sites as to treatment group isbeing maintained in two ways. Study medication is masked by placing thetreatment kits including study medication and supplies for the posteriorjuxtascleral administration in sealed opaque boxes identified by patientnumber only. The boxes were numbered sequentially at each clinical siteand patients were assigned the next available sequential number uponenrollment. The randomization was built into the sequential numbering ofthe treatment kits and blocked within each site to maintain equaldistribution across treatment assignments. Masking as to treatment groupis also being maintained at each site by having an unmasked injectinginvestigator perform the treatments and a masked examining investigatorperform the subsequent evaluations. Upon enrollment of each patient,anecortave acetate or placebo was administered behind the eye as a 0.5mL posterior juxtascleral injection onto the outer surface of the scleranear the macula using a specially designed cannula. The cannula isdescribed in commonly owned U.S. Pat. No. 6,413,245B 1.

Clinical efficacy data is being obtained from evaluations ofbest-corrected log MAR visual acuity and standardized fluoresceinangiograms. Clinical safety data obtained from general physicalexaminations, laboratory evaluations of blood and urine, and completeophthalmic examinations, including indocyanine green angiography,continue to be periodically evaluated by the Independent SafetyCommittee overseeing this study. Clinical data from evaluations forsafety and efficacy performed at Day 1-2, Week 2, Week 6, Month 3, andMonth 6 following patient randomization and treatment are reported here.

The primary efficacy outcome for this ongoing study is the mean changefrom Baseline in best-corrected log MAR visual acuity. Secondaryefficacy outcomes are: the percentage of patients with preservation ormaintenance of vision (defined as loss of less than three log MAR lines[less than 15 log MAR letters] of visual acuity); the percentage ofpatients with clinically significant worsening of vision (defined as aloss of at least three log MAR lines [at least 15 log MAR letters] ofvisual acuity); the percentage of patients with severe vision loss(defined as a loss of at least six log MAR lines [at least 30 log MARletters] of visual acuity); and changes in CNV lesion characteristics(defined as total lesion area, total CNV and total classic CNV).

All efficacy analyses were based on the intent-to-treat principle. Allpatients received the medication to which they were assigned, and wereanalyzed accordingly. Last-observation-carry-forward was used to imputemissing values. Baseline comparisons were tested using analysis ofvariance (for continuous outcomes) and Pearson's chi square (for binaryoutcomes). Changes from baseline in visual acuity and lesion parameterswere tested in a repeated measures analysis of variance model withappropriate contrasts for the 6-month comparisons. Comparisons of binaryoutcomes at Month 6 were evaluated using Pearson's chi-square tests. Allanalyses of ocular outcomes are based on changes in the study (i.e.,treated) eye.

In this ongoing study, re-treatment with study medication is beingperformed by the unmasked injecting investigator if the masked examininginvestigator judges that the patient may benefit. A 6-month re-treatmentinterval was established for this ongoing study based upon preclinicaldata demonstrating that anecortave acetate administered as aslow-release depot adjacent to the posterior scleral surface providedtherapeutic drug levels in the adjacent choroid and retina for up to 6months (data not shown). Sixty-two (62) of the 128 patients enrolled inthis study have received at least three posterior juxtascleraladministrations of anecortave acetate or placebo at 6-month intervalswhile 16 patients have received at least five such treatments. As ofAugust 2002, 50 patients continue to be treated with masked studymedication at 6-month intervals in this ongoing study. However, theefficacy results presented here are based upon a single (initial)administration of study medication.

There were no statistically significant differences in Baseline valuesamong treatment groups with respect to age, sex, race, log MAR visualacuity, or lesion characteristics (Table 2). The original study designallowed treatment of predominantly classic subfoveal lesions only, butthe protocol was later amended to also allow enrollment and treatment ofminimally classic lesions. Of the 128 patients in this study, 80% (102of 128) entered the study with predominantly classic lesions while 20%(26 of 128) entered with minimally classic lesions. A predominantlyclassic lesion is defined as one in which classic CNV occupies at least50% of the area of the total lesion (defined for this study asangiographic evidence of neovascularization, associated contiguous areasof serous elevation of the RPE, elevated blocked fluorescence, bloodand/or late staining). The Baseline patient characteristics in thisstudy were generally similar to those reported for the Visudyne® TAPtrial (2), except that more (80% vs. 40%) of the patients in the studyreported here had predominantly classic lesions at Baseline.

An interim analysis of all 128 patients was performed to evaluate meanchange at Month 6 from Baseline values in log MAR visual acuity (FIG.1). Anecortave acetate 15 mg is statistically superior to placebotreatment (p=0.0032) at Month 6. Trends also favor treatment with bothanecortave acetate 30 mg and 3 mg over placebo treatment, althoughstatistical significance is not achieved. Anecortave acetate 15 mgexhibits the greatest efficacy for stabilizing vision of the fourgroups.

As a secondary visual outcome, the percentage of patients withpreservation of vision at Month 6 was analyzed. Preservation(maintenance) of vision, defined as a decrease of less than three logMAR lines of visual acuity from Baseline values, is accepted as aclinically relevant measure of efficacy and has been used as a primaryoutcome variable in a previous report evaluating therapy for subfovealAMD (2). The 6-month results of this analysis are presented in FIG. 2.There was greater preservation of vision at month six for patientstreated with anecortave acetate 15 mg than for placebo, although theresults did not achieve statistical significance at the p=0.05 level.Whereas 88% of patients treated with anecortave acetate 15 mg preservedvision at Month 6, only 70% of placebo-treated patients showed a similarpositive visual outcome. However, as shown in FIG. 3, analysis of thesedata in the large subgroup of patients with a predominantly classic CNVlesion revealed a significant benefit favoring anecortave acetate 15 mg,with 92% of patients treated with anecortave acetate 15 mg preservingvision at Month 6 versus 65% of patients in the placebo group(p=0.0209). The efficacy of anecortave acetate 15 mg for preservingvision is further supported by data comparing clinically significantvision loss among treatment groups (Table 3). There is statisticalsuperiority of anecortave acetate 15 mg at Month 6 compared with placebo(p=0.0224) for the prevention of severe vision loss (Table 4).

FIG. 4 shows the results of an analysis of the percentage of patientswith an improvement at month six of at least 2 log MAR lines in visualacuity from Baseline values. Eighteen percent (18%) of patients treatedwith anecortave acetate 15 mg improved by at least 2 log MAR linescompared with 3% of patients in the 30 mg group, 6% in the 3 mg group,and 0% in the placebo group. The difference between anecortave acetate15 mg and placebo was statistically significant (p=0.025).

Because of preclinical data demonstrating anecortave acetate'sangiostatic efficacy, CNV lesion changes from Baseline values in surfaceareas were analyzed. Total lesion areas, total CNV areas, and totalclassic CNV areas were measured and compared among treatment groups.While the average lesion size was similar among the treatment groups atBaseline, the variability within treatment groups reduced thesensitivity to demonstrate group differences when the groups wereanalyzed for mean change from Baseline values. Changes in these lesioncharacteristics were therefore analyzed as percent change from Baselinevalues, which proved to be a more sensitive measure for evaluating apopulation of lesions which ranged from 0.28 mm² to 33.25 mm² in totallesion areas at Baseline. As shown in FIG. 5, treatment with anecortaveacetate 15 mg is statistically superior to placebo treatment forinhibition of total lesion surface area (p=0.0005), total CNV surfacearea (p=0.0001), and total classic CNV surface area (p=0.0008) at Month6. In addition, there is a trend favoring anecortave acetate 30 mg and 3mg treatment over placebo treatment for inhibition of lesion growth.

Following completion of the Month 6 visit by all patients, theaccumulated safety data were evaluated by the Independent SafetyCommittee overseeing this study. Based upon this evaluation, noclinically relevant medication-related or administration-related safetyconcerns were identified. The most common ocular changes reported werechanges in lens opacity using the Lens Opacity Classification System(LOCS) II, and included reports of nuclear color, nuclear opalescence,cortical, and posterior subcapsular changes. Cataracts are a commonintercurrent disorder in this patient population, and the changes seenwere documented in all treatment groups and in contralateral (untreated)eyes. The cataractous changes reported were described as mild andtypically unrelated to treatment. The second most common ocular change,a decrease in vision (defined as a decrease of ≧4 log MAR lines from theprevious visit), is also a common problem in this patient population.These vision decreases occurred in all treatment groups and in thecontralateral eye. Other ocular changes (occurring with a frequencygreater than 5%) were ptosis, ocular pain, subconjunctival hemorrhage,ocular pruritis, ocular burning/stinging, pupil disorders, foreign bodysensation, ocular hyperemia, and abnormal vision. These changes werereported in all four treatment groups, in both treated eyes andcontralateral eyes, were characterized as primarily mild, were generallynot attributed to treatment, and were transient in nature. The singlereport of an IOP increase (≧10 mmHg) from Baseline occurred in a patienttreated with anecortave acetate 30 mg and was attributed to intercurrentillness. Of the ocular changes reported, those most frequentlyattributed to study treatment were ptosis, ocular pain, subconjunctivalhemorrhage, ocular pruritis, and ocular burning/stinging. Thesetreatment-related events were mostly mild, transient, and seen withinall four treatment groups.

The most common non-ocular changes from Baseline reported for this studywere hypertension, peripheral edema, depression, and arthritis, none ofwhich were attributed to treatment. No treatment-related changes inblood chemistry, hematology, or urinalysis were reported.

The data reported here are the result of an interim analysis of thefirst 6 months of clinical data from the ongoing study evaluatinganecortave acetate as monotherapy for treatment of exudative AMD. Thisanalysis demonstrates that a single posterior juxtascleraladministration of anecortave acetate 15 mg is a safe and effectivetreatment for preserving or improving vision as well as preventingsevere vision loss. These data also show that anecortave acetateinhibits lesion growth in patients with subfoveal CNV secondary to AMD.While there is a trend favoring a single administration of each of thethree concentrations of anecortave acetate over placebo treatment, asingle administration of anecortave acetate 15 mg is statisticallysuperior to placebo for both functional and anatomical measures ofclinical efficacy.

Anecortave acetate is an angiostatic agent developed for the inhibitionof ocular neovascularization. Anecortave acetate is the result ofspecific chemical modification to the basic cortisol structure. Thesemodifications have resulted in the creation of an angiostatic“cortisene,” which inhibits blood vessel growth, but does not produceglucocorticoid receptor-mediated steroidal side effects. Preclinicaldata show that anecortave acetate exhibits no measurable corticosteroidactivity (8,9) and there is no clinical evidence of ocularcorticosteroid side effects (such as elevated intraocular pressure oraccelerated cataract progression) in the study reported here. Followingan evaluation of safety data from patients with at least 6 months ofanecortave acetate exposure, the Independent Safety Committee identifiedno clinically relevant drug-related or procedure-related safety issues.

Anecortave acetate is a unique angiostatic agent that upregulatesplasminogen activator inhibitor 1 and inhibits both urokinase-likeplasminogen activator and matrix metalloproteinase-3, two enzymesnecessary for vascular endothelial cell migration during blood vesselgrowth (5,6). Preclinical data in models of corneal, retinal, andchoroidal neovascularization support the efficacy of this agent for theinhibition of vessel growth (5,6,8-10).

The interim analysis of clinical data reported here demonstrateangiostatic efficacy at Month 6 following a single posteriorjuxtascleral administration, based on the masked evaluation ofstandardized fluorescein angiograms by DARC, the central reading centerused for this study. This analysis shows that anecortave acetate 15 mgis statistically superior to placebo at Month 6 for inhibition of lesiongrowth. There was inhibition not only of total lesion growth but also ofthe CNV component and the classic CNV lesion component.

Analysis of the Month 6 data demonstrate a trend favoring anecortaveacetate 15 mg over placebo treatment for preservation of vision in theoverall analysis, and statistical superiority for preserving vision inthe large subgroup of patients with predominantly classic lesions.Anecortave acetate 15 mg is also statistically superior to placebo forvision improvement, defined as an improvement of 2 or more lines of logMAR visual acuity. Conversely, a single treatment with anecortaveacetate 15 mg inhibits both clinically significant vision loss andsevere vision loss at Month 6 compared with placebo treatment.

The superiority of anecortave acetate 15 mg dose compared with placebofor stabilizing vision is demonstrated by the analysis of mean change atMonth 6 from Baseline log MAR vision. Although the mean Baseline log MARvision was very similar for the anecortave acetate 15 mg and placebogroups (0.73 vs. 0.76, respectively, or 20/100 Snellen equivalent), thevision outcome at Month 6 was distinctly different for these twotreatment groups. After treatment with a single administration ofanecortave acetate 15 mg, the mean vision changed by only 4 log MARletters at Month 6, resulting in an average final log MAR value of 0.81(20/125 Snellen equivalent). However, the placebo group over the sameperiod worsened by more than 12 log MAR letters, resulting in an averagefinal value of 1.01 (20/200 Snellen equivalent). This 2-line differencebetween groups in log MAR visual acuity is likely to have implicationsfor the daily activities of a patient with subfoveal AMD.

All three doses of anecortave acetate have been shown here to be safe,and following a single administration there is a trend at Month 6favoring the three doses for inhibition of lesion growth, forpreservation of vision, and for prevention of severe vision loss. Theclinical data reported here suggest the 15 mg dose is at or near the topof the biological dose-response curve for this molecule, and higherconcentrations are not likely to be associated with greater efficacy invivo. Alternatively, there may be differences in the formation andphysical structure of the slow-release drug depot on the posteriorscleral surface resulting from the different concentrations of drugsuspension evaluated in this study which could in some way affect theabsorption of the anecortave acetate into the overlying choroid andretina.

The clinical efficacy of anecortave acetate 15 mg compared with placebofor prevention of both clinically significant vision loss (defined as aloss of 15 or more log MAR letters) and severe vision loss (defined as aloss of 30 or more log MAR letters) at Month 6 is at least comparable tosimilar Month 6 data reported for the Visudyne® TAP study (2). In viewof the consistent superiority of a single administration of anecortaveacetate 15 mg compared with placebo treatment for preservation of visionand for inhibition of lesion growth, a pivotal study has been initiatedto compare anecortave acetate 15 mg with Visudyne® PDT. This study isnow enrolling patients, and includes 40-50 clinical sites in NorthAmerica, Australia and the European Union.

It should be appreciated that anecortave acetate or its correspondingalcohol (4,9(11)-pregnadien-17α,21-diol-3,20 dione) can also beadministered via a juxtascleral implant as described, e.g., in thefollowing commonly owned patents and patent applications: U.S. Pat. No.6,413,540B1; U.S. Pat. No. 6,416,777B1; WO/03/009784; and WO/03/009774.Juxtascleral administration via depot or by any other method providesfor transcleral delivery of the drug. It can also be administered by anintravitreal injection or an implant, such as the one described in aco-pending U.S. application Ser. No. 10/385,791.

All patents and other references referred to herein are herebyincorporated by reference.

REFERENCES

-   1. Seddon J M. Epidemiology of age-related macular degeneration.    Retina, Ryan S J (ED.). St. Louis: Mosby, 2001; 1039-50.-   2. Treatment of Age-related Macular Degeneration with Photodynamic    Therapy (TAP) Study Group. Photodynamic therapy of subfoveal    choroidal neovascularization in age-related macular degeneration    with verteporfin—TAP Report 1. Arch. Ophthalmol. 1999; 117: 1329-45.-   3. The EyeTech Study Group. Preclinical and phase IA clinical    evaluation of an anti-VEGF pegylated aptamer (EYE001) for the    treatment of exudative age-related macular degeneration. Retina    2002; 22: 143-52.-   4. Krzystolik M G, Afshari M A, Adamis A P, et al. Prevention of    experimental choroidal neovascularization with intravitreal    anti-vascular endothelial growth factor antibody fragment. Arch.    Ophthalmol. 2002; 120: 338-46.-   5. DeFaller J M and Clark A F. A new pharmacological treatment for    angiogenesis. In Pterygium, Taylor, H R (ED.) The Hague: Kugler    Publications, 2000; 159-181.-   6. Penn J S, Rajaratnam V S, Collier R J and Clark A F. The effect    of an angiostatic steroid on neovascularization in a rat model of    retinopathy of prematurity. Invest. Ophthalmol. Vis. Sci. 2001; 42:    283-90.-   7. Casey R, Li W W. Factors Controlling Ocular Angiogenesis.    Amer. J. Ophthalmol. 1997; 124: 521-529.-   8. Clark A F. AL-3789: a novel ophthalmic angiostatic steroid. Exp.    Opin. Invest. Drugs 1997; 6: 1867-77.-   9. McNatt L G, Weimer L, Yanni J and Clark A F. Angiostatic activity    of steroids in the chick embryo CAM and rabbit cornea models of    neovascularization. J. Ocular Pharm. Therap. 1999; 15(5): 413-23.-   10. BenEzra D, Griffin B W, Naftzir G, Sharif N A and Clark A F.    Topical formulations of novel angiostatic steroids inhibit rabbit    corneal neovascularization. Invest. Ophthalmol. Vis. Sci. 1997; 38:    1954-62.

This invention has been described by reference to certain preferredembodiments; however, it should be understood that it may be embodied inother specific forms or variations thereof without departing from itsspecial or essential characteristics. The embodiments described aboveare therefore considered to be illustrative in all respects and notrestrictive, the scope of the invention being indicated by the appendedclaims rather than by the foregoing description. TABLE 1 PatientInclusion and Exclusion Criteria Inclusion Criteria Patient must bewilling to give and sign informed consent, able to make the requiredstudy visits, and able to follow instructions. Patient must be at least50 years of age Patients may be of any race and either sex. Femalepatients of childbearing potential (those who are not postmenopausal orsurgically sterile) may participate only if they are not lactating, ifthey have a negative pregnancy test at the Eligibility Visit and priorto each of the three subsequent injections, and if they agree to useadequate birth control methods (hormonal - oral, implantable orinjectable chemical contraceptives; mechanical - spermicide inconjunction with a barrier such as condom or diaphragm; IUD; or surgicalsterilization of partner) to prevent pregnancy throughout the 24 monthstudy. Urine pregnancy tests will be performed prior to each treatment,at each Month 3 post-treatment Visit, and at the Exit Visit on allfemale patients of childbearing potential. Male patients whose partneris of child bearing potential should also use a reliable means to avoidfathering a child while taking part in this study because the effect thestudy drug may have on sex cells and what effect this would have on thedevelopment of an unborn child is unknown. Clinical diagnosis ofexudative age-related macular degeneration and a primary or recurrentsubfoveal neovascular membrane which does not meet MPS laserphotocoagulation treatment guidelines and which has the followingcharacteristics as defined below: A total lesion size of 12 disc areasor less, AND 50% or more of the total lesion (defined as angiographicevidence of neovascularization, associated contiguous areas of serouselevation of the RPE, elevated blocked fluorescence, and/or latestaining) is choroidal neovascularization (CNV), AND EITHER The classiccomponent of the total CNV is ≧50% of the total choroidalneovascularization, OR The classic component of the total CNV is ≧0.75disc areas (1.6 mm²) Clinical diagnosis of exudative age-related maculardegeneration and a primary or recurrent subfoveal neovascular membrane(with the physical characteristics described above) which is eligiblefor laser photocoagulation treatment by the most current MPS guidelinesbut for which the patient has formally declined this approved treatmentin writing. Best-corrected ETDRS visual acuity of 0.3 (20/40 Snellen) to1.2 (20/320 Snellen) in the study eye at the Eligibility Visit. Thecontralateral (“nonstudy”) eye must have a best-corrected ETDRS visualacuity of 1.6 (20/800 Snellen) or better and clinical evidence ofmacular degeneration (i.e., drusen, changes in the retinal pigmentedepithelium or signs of exudative disease or disciform scarring).Exclusion Criteria Patient has a history of any medical condition whichwould preclude scheduled study visits or completion of the study (i.e.,unstable cardiovascular disease, unstable pulmonary disease or AIDS).Patient has a history of ophthalmic disease in the study eye (other thanARMD) that would likely compromise or during follow-up could likelycompromise the visual acuity of the study eye (i.e., amblyopia,uncontrolled glaucoma with an IOP >30 mmHg, ischemic optic neuropathy,clinically significant diabetic macular edema, significantnon-proliferative or proliferative diabetic retinopathy, significantactive uveitis). Patient's screening fluorescein angiographic imagesand/or indocyanine green angiographic images cannot be adequatelyvisualized by the investigator and the Digital Angiography ReadingCenter. Patient exhibits clinical signs of myopic retinopathy, or has arefraction of >−8 diopter power in their current prescription. Patienthas had intraocular surgery in study eye less than two (2) months priorto enrolling in the study. Patient has a history of a previousexperimental procedure for the treatment of AMD in the study eye(excluding daily vitamin and/or mineral therapy) other than laserphotocoagulation treatment for exudative ARMD in the study eye. Patienthas had insertion of a scleral buckle in the study eye Use of anyinvestigational drug or treatment related or unrelated to ARMD within 30days prior to receipt of study medication, excluding daily vitaminand/or mineral therapy. Patient has a known medical history of allergyor sensitivity to the steroid family of drugs, or to fluorescein and/orindocyanine green dyes that is clinically significant in theinvestigator's opinion. Patient has received radiation treatment (otherthan proton beam radiation) or systemically administered anti-angiogenictherapy for exudative ARMD in either eye. Patients with history ofproton beam treatment of fellow eye only may be enrolled in this study.Patient is on anticoagulant therapy, with the exception of aspirin andantiplatelet therapy. Patient has a medical history of a bleedingdisorder. Patient has clinical evidence of scleral thinning.

TABLE 2 Baseline Patient Characteristics Anec Acet Anec Acet Anec Acet30 mg 15 mg 3 mg Placebo (n = 33) (n = 33) (n = 32) (n = 30) N % N % N %N % P-value Age (years) <65 4 12.1 5 15.2 1 3.1 0 0.0 0.3349 65-74 721.2 7 21.2 9 28.1 8 26.7 75-84 19 57.6 17 51.5 15 46.9 19 63.3 85-93 39.1 4 12.1 7 21.9 3 10.0 Female 18 54.5 18 54.5 15 46.9 18 60.0 0.7781Caucasian 33 100.0 33 100.0 32 100.0 30 100.0 — Total Lesion ClassicComponent* <50% Classic 7 21.2 8 24.2 7 21.9 4 13.3 0.7333 ≧50% Classic26 78.8 25 75.8 25 78.1 26 86.7 Age - Mean (SD) 75.7 (7.5)  75.8 (8.3) 78.1 (7.5)  78.3 (5.8)  0.3193 logMAR VA - Mean (SD) 0.72 (0.26) 0.73(0.26) 0.83 (0.24) 0.76 (0.26) 0.2859 Total Lesion mm² - Mean (SD) 8.6(6.9) 7.4 (6.6) 9.0 (7.5) 6.9 (5.7) 0.5796 CNV mm² - Mean (SD) 7.4 (6.0)6.4 (5.5) 7.9 (7.0) 6.0 (5.2) 0.5721 Classic mm² - Mean (SD) 5.7 (5.3)5.0 (5.0) 5.3 (4.7) 4.2 (4.2) 0.6847*Determined from the ratio of the size of the classic component to thesize of the total lesion.

TABLE 3 Clinically Significant logMAR Vision Changes at Month 6 LogMARChange ≧2 Lines 1 Line No 1 Line 2 Lines ≧3 Lines Improved ImprovedChange Worsened Worsened Worsened N % N % N % N % N % N % Anec Acet 30mg 1 3.0 4 12.1 10 30.3 5 15.2 5 15.2 8 24.2 Anec Acet 15 mg 6 18.2 13.0 8 24.2 4 12.1 10 30.3 4 12.1 Anec Acet 3 mg 2 6.3 0 0 12 37.5 4 12.56 18.8 8 25.0 Placebo 0 0 2 6.7 11 36.7 4 13.3 4 13.3 9 30.0

TABLE 4 Severe Vision Loss (≧6 logMAR lines) at Month 6 Total <6 LinesWorse ≧6 Lines Worse Treatment N N % N % Anec Acet 30 mg 33 25 75.76 824.24 Anec Acet 15 mg 33 32 96.97 1 3.03 Anec Acet 3 mg 32 25 78.13 721.88 Placebo 30 23 76.67 7 23.33 Total 128 105 82.03 23 17.97p = .0224, Anec Acet 15 mg vs. Placebo, Fisher's Exact Test

1. A method for the prevention of the loss of visual acuity associatedwith AMD, which comprises, administering a pharmaceutically effectiveamount of the compound anecortave acetate or its corresponding alcohol,wherein said administering is by a method selected from the groupconsisting of posterior juxtascleral injection, juxtascleral implant,intravitreal injection, or implant.
 2. The method of claim 1, whereinthe compound is administered as a juxtascleral depot.
 3. The method ofclaim 2, wherein the depot comprises 3 mg-30 mg of compound.
 4. Themethod of claim 3, wherein the depot comprises 15 mg of compound.
 5. Amethod for maintaining visual acuity in a person suffering from AMD,which comprises administering a pharmaceutically effective amount of thecompound anecortave acetate or its corresponding alcohol, wherein saidadministering is by a method selected from the group consisting ofposterior juxtascleral injection, juxtascleral implant, intravitrealinjection, or implant.
 6. The method of claim 5, wherein the compound isadministered as a juxtascleral depot.
 7. The method of claim 6, whereinthe depot comprises 3 mg-30 mg of compound.
 8. The method of claim 7,wherein the depot comprises 15 mg of compound.
 9. A method for theinhibition of lesion growth associated with AMD, which comprisesadministering a pharmaceutically effective amount of the compoundanecortave acetate or its corresponding alcohol, wherein saidadministering is by a method selected from the group consisting ofposterior juxtascleral injection, juxtascleral implant, intravitrealinjection, or implant.
 10. The method of claim 9, wherein the compoundis administered as a juxtascleral depot.
 11. The method of claim 10,wherein the depot comprises 3 mg-30 mg of compound.
 12. The method ofclaim 11, wherein the depot comprises 15 mg of compound.
 13. The methodof any one of claims 1, 5, or 9, wherein the compound is administered ina juxtascleral implant.
 14. The use of anecortave acetate or itscorresponding alcohol for the preparation of a medicament for theprevention of the loss of visual acuity associated with AMD.
 15. The useof anecortave acetate or its corresponding alcohol for the preparationof a medicament for maintaining visual acuity in a person suffering fromAMD.
 16. The use of anecortave acetate or its corresponding alcohol forthe preparation of a medicament for the inhibition of lesion growthassociated with AMD.
 17. The use according to claims 14-16 wherein thepreparation is administered as a juxtascleral depot.
 18. The useaccording to claim 17 wherein the depot comprises 3 mg-30 mg ofanecortave acetate or its corresponding alcohol.
 19. The use accordingto claim 18 wherein the depot comprises 15 mg of anecortave acetate orits corresponding alcohol.
 20. The use according to claims 14-16 whereinthe preparation is administered as a juxtascleral implant.
 21. A methodfor inhibiting blood vessel growth associated with AMD, said methodcomprising administering a pharmaceutically effective amount of thecompound anecortave acetate or its accompanying alcohol, wherein theadministering is by juxtascleral injection, intravitreal injection,juxtascleral implant, or other implant.
 22. The method of claim 21,wherein the amount of compound administered is from 3 mg to 30 mg. 23.The method of claim 22, wherein the amount of compound administered is15 mg.
 24. The method of claim 9, wherein the lesion is a predominantlyclassic subfoveal lesion.
 25. The method of claim 9, wherein the lesionis a minimally classic lesion.